US4069326A - Morpholino containing indane acetic acid esters - Google Patents
Morpholino containing indane acetic acid esters Download PDFInfo
- Publication number
- US4069326A US4069326A US05/690,391 US69039176A US4069326A US 4069326 A US4069326 A US 4069326A US 69039176 A US69039176 A US 69039176A US 4069326 A US4069326 A US 4069326A
- Authority
- US
- United States
- Prior art keywords
- sub
- indanyl
- acetic acid
- methyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/194—Radicals derived from thio- or thiono carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/34—Monohydroxylic alcohols containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/50—Halogenated unsaturated alcohols containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- the present invention relates to certain indane derivatives, to processes for their preparation and to their use in therapy.
- the present invention provides a compound of general formula: ##STR2## in which:
- X represents a hydrogen or halogen atom
- R 1 and R 2 which may be identical or different, each represents a hydrogen atom an alkyl group containing 1 to 5 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms
- R 3 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms
- Y represents --CH 2 OH or a group of formula --COOR 4 in which R 4 represents a hydrogen atom, 1/v (M) where M is a metal of valency v, or a group of formula:
- n is an integer of 1 to 5 and R 5 and R 6 , which may be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms, an aryl group or an aralkyl group, or R 5 and R 6 , together with the nitrogen atom to which they are bonded, form an N-heterocyclic group with 5 to 7 ring members, which heterocyclic group optionally contains a second heteroatom (e.g. a nitrogen, oxygen or sulphur atom) and/or one or more substituents (e.g. alkyl groups containing 1 to 5 carbon atoms), or a pharmaceutically acceptable addition salt of a compound of formula (I).
- a second heteroatom e.g. a nitrogen, oxygen or sulphur atom
- substituents e.g. alkyl groups containing 1 to 5 carbon atoms
- the aforesaid alkyl groups of 1 to 5 carbon atoms may be straight or branched; similary, the group --CH 2 ) n may be straight or branched.
- the cycloalkyl groups of 3 to 7 carbon atoms may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, cyclohexyl being preferred.
- the substituents R 1 and R 2 may be on the same or different carbon atoms of the indane nucleus.
- the metal M is preferably from group I, II or III of the periodic classification; sodium, potassium, calcium and aluminium are especially suitable.
- Suitable N-heterocyclic groups --NR 5 R 6 include, more especially, pyrrolidino, morpholino, thiomorpholino, 3,5-dimethyl-morpholino, piperidino, 4'-methyl-piperidino, piperazino, 4-( ⁇ -hydroxyethyl)-piperazino, 4-p-chlorophenyl-piperazino and azepino.
- R 4 is an aryl group, it may be, for example, phenyl, and when it is aralkyl, it may be, e.g. ⁇ -phenylethyl, ⁇ -phenylethyl, or benzyl.
- the invention includes the addition salts of the compounds of the formula I, especially the addition salts with amines when R 4 is hydrogen and the addition salts with acids or quaternary ammonium salts when R 4 is --(CH 2 ) n NR 5 R 6 .
- the addition salts with acids may be produced by reaction of the base with an inorganic or organic acid in manner known per se.
- Suitable acids for this purpose are, more especially, hydrochloric, sulphuric, phosphoric, oxalic, succinic, methanesulphonic, cyclohexylsulphamic, formic, aspartic, glutamic, N-acetyl-aspartic, N-acetyl-glutamic, ascorbic, maleic, malic, fumaric, lactic, benzoic, cinnamic and p-toluenesulphonic acids.
- Particularly preferred compounds of formula (I) are those in which R 1 and R 2 each represents a hydrogen-atom or a methyl, ethyl isopropyl or cyclohexyl group, R 3 represents a hydrogen atom or a methyl or ethyl group and X represents a hydrogen atom. If Y represents a group of formula --COOR 4 , R 4 is preferably a hydrogen atom or a group of formula ##STR3##
- step a) is the chloride and the preferred compounds of formula R 3 MgZ for use in step (c) are those in which Z is iodine.
- step (a) may be carried out under typical Friedel-Crafts' reaction conditions in the presence of a Lewis acid such as AlCl 3 and a solvent such as ethylene chloride and step (b) may be carried out using hydrazine in a solution containing sodium or potassium ions.
- step (c) is suitably carried out in an ether solvent
- the dehydration of the compound of formula VII may be carried out using a strong acid such as concentrated sulphuric acid and the final hydrogenation is suitably carried out in the presence of a catalyst, for example Raney nickel.
- Process (A) is illustrated by the following reaction scheme: ##STR10##
- a nitrile of formula (IVa) in which R 3 represents an alkyl group containing 1 to 5 carbon atoms can be obtained by reacting a nitrile of formula (IVa) in which R 3 represents a hydrogen atom with a metallating agent such as sodium or potassium hydride or amide or potassium tert-butylate and reacting the resulting compound of formula: ##STR12## in which M is an alkali metal atom, with a halide of formula R 3 Z in which R 3 represents an alkyl group containing 1 to 5 carbon atoms and Z is a halogen atom, preferably bromine or iodine.
- Step (a) is preferably carried out using hydrochloric acid and formaldehyde or trioxymethylene.
- step (D) may be carried out using method known in the art; step (a) may be carried out under typical Friedel-Crafts' reaction conditions, step (b) may be carried out using conventional reducing agents suitable for reducing a ketone to an alcohol, for example an alkali metal borohydride or lithium aluminium hydride, and step (c) may be carried out using, for example, phosphorus tribromide or thionyl chloride.
- step (a) may be carried out under typical Friedel-Crafts' reaction conditions
- step (b) may be carried out using conventional reducing agents suitable for reducing a ketone to an alcohol, for example an alkali metal borohydride or lithium aluminium hydride
- step (c) may be carried out using, for example, phosphorus tribromide or thionyl chloride.
- This process involves a Willgerodt reaction (a variation of the Kindler reaction).
- the ketones of formula (X) in which X represents a hydrogen atom can be obtained by step (a) of process (D).
- the hydrolysis of the thioamide is preferably carried out under acid conditions.
- the compounds of formula (I) in which Y represents a --CH 2 OH group can be prepared by methods including the step of reducing a compound of formula: ##STR25## in which R 1 , R 2 , R 3 and X are as hereinbefore defined and R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms.
- the compounds of formula (XVI) in which R is hydrogen can be prepared by any of the processes (A) to (E) described above and the compounds in which R is an alkyl group can be obtained by conventional esterification of the corresponding acid.
- the reduction can be carried out by means of a reducing agent, for example, lithium aluminium hydride, in an organic solvent such as ether or tetrahydrofuran.
- the compounds of the invention and their nontoxic addition salts possess valuable pharmacological activities and are useful in therapy, especially as analgesic and anti-inflammatory agents. They can, for example, be used as anti-inflammatory agents for counteracting rheumatism.
- compositions which are especially useful in the treatment of inflammations and algias, rheumatisms and pain syndromes which compositions comprise a pharmaceutically effective amount of at least one compound of formula (I) or one of its non-toxic addition salts and a pharmaceutically acceptable carrier or diluent.
- the compounds of formula (I) can, for example, be administered to man in the form of gelatine-coated pills containing 50 to 250 mg of active principle at a dose of 2 to 6 gelatine-coated pills per day, in the form of suppositories containing 100 to 500 mg of active principle at a daily dose of 2 to 5 suppositories per day, in the form of a potable suspension containing 25 mg of active principle per 5 cm 3 at a daily dose of 10 to 40 cm 3 or in the form of an injectable solution containing 50 mg of active principle per 2 ml of solution at a daily dose of 2 to 4 injections.
- the compounds of formula (I) possess an LD50 in rats of approximately 250 mg/kg when administered orally, have little tendency to cause ulcers, and possess an activity to toxicity ratio which is generally higher than that of the known products possessing similar pharmacological properties.
- Examples 2 to 7 and 11 to 18 illustrate process A
- Example 1 illustrates process C
- Example 26 illustrates process D
- Example 36 illustrates process E
- Examples 8, 9 and 21 to 32 illustrate process F
- Examples 33 to 35 and 37 illustrate the preparation of compounds in which Y is --CH 2 OH
- Examples 19 and 20 illustrate the preparation of addition salts.
- reaction mixture After evaporation of the ethanol in vacuo, the reaction mixture is diluted with 200 ml of water and then filtered. The filtrate is acidified at 0° by means of 10% strength hydrochloric acid and the precipitate formed is filtered off, washed with water and dried. After recrystallisation from toluene, 20 g of [1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
- Example 2(a) Following the procedure of Example 2(a) but using 50 g of 1,3-dimethyl-6-chloro-indane and 43 g of ethyloxalyl chloride, 80 g of ethyl [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
- Example 2(c) following the procedure of Example 2(c) but starting from 20 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylic acid, 10.5 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from toluene. Melting point 158°-160° C.
- Example 2(b) Following the procedure of Example 2(b) but starting from 69 g of ethyl [2-isopropyl-indanyl-(5)]-glyoxylate, 58 g of 2-[2-isopropyl-indanyl-(5)]-glyoxylic acid are obtained in the form of pale yellow crystals, recrystallised from a 50/50 mixture of hexane and cyclohexane. Melting point 55°-60° C.
- Example 2(a) Following the procedure of Example 2(a) but using 70 g of 1-cyclohexyl-indane and 54.6 g of ethyloxalyl chloride, 110 g of ethyl [1-cyclohexyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
- the Grignard reagent prepared from 34.2 g of magnesium in 75 ml of ether and 105 ml of methyl iodide in 200 ml of ether, is added dropwise to a solution, cooled in ice, of 65.5 g of [1,3-dimethyl-indanyl-(5)]-glyoxylic acid in 900 ml of ether. The addition lasts for 1 hour.
- the reaction mixture is then stirred at the temperature of the laboratory for 2 hours and is then poured onto 2 kg of ice and acidified by means of 10% strength hydrochloric acid. The mixture is extracted with ethyl acetate and the extract is washed with water and dried. After evaporation of the solvent, 53 g of 2-hydroxy-2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid are obtained and are used in crude form for the remainder of the operations.
- Example 8(b) following the procedure of Example 8(b) but using 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride prepared from 10 g of acid, 7 g of the morpholino-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained. After adding 2.55 g of oxalic acid in acetone and recrystallising from acetone, 7.3 g of the oxalate are obtained in the form of white crystals.
- a solution of 100 g of 2-isopropyl-indane and 65 ml of acetic anhydride in 400 ml of methylene chloride is added over the course of 1 hour to a stirred suspension of 190 g of aluminium chloride in 400 ml of methylene chloride, whilst cooling in such a way that the temperature of the reaction mixture remains below 10° C.
- the mixture is then stirred for 5 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified to pH 3 by means of hydrochloric acid.
- the methylene chloride phase is isolated and the mother liquors are extracted with methylene chloride.
- the methylene chloride phases are combined, washed with water and dried over sodium sulphate.
- Boiling point 1 .5 mm Hg 121°-125° C.
- ⁇ -[2-Isopropyl-indanyl-(5)]-ethanol 25.6 g of potassium borohydride are added in small portions to a solution of 105.5 g of [2-isopropyl-indanyl-(5)]-methyl ketone in 600 ml of methanol. After the reaction mixture has been stirred magnetically at the temperature of the laboratory for 3 hours, it is concentrated in vacuo, ice is added to it, and the organic products are extracted with ether. After washing with water and drying over sodium sulphate, the ether is evaporated. 106 g of ⁇ -[2-isopropyl-indanyl-(5)]-ethanol are thus obtained and are used in crude form for the remainder of the operations.
- Boiling point 1 .5 mm Hg 132°-136° C.
- Boiling point 1 .5 mm Hg 135°-150° C.
- a solution of 110.3 g of 2-cyclohexyl-indane and 86 g of ethyloxalyl chloride in 400 ml of methylene chloride is added over the course of 1 hour to a stirred suspension of 128 g of aluminium chloride in 400 ml of methylene chloride, whilst cooling in such a way that the temperature of the reaction mixture remains below 5° C.
- the mixture is then stirred for 2 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified to pH 3 by means of hydrochloric acid.
- the methylene chloride phase is isolated and the mother liquors are extracted with methylene chloride.
- the methylene chloride phases are combined, washed with water saturated with sodium chloride and dried over sodium sulphate.
- a mixture of 40 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid and 100 ml of hydrazine hydrate is heated under reflux for 45 minutes.
- the mixture is cooled to 70° C and 50 g of potassium hydroxide pellets are added in small portions.
- the mixture is heated under reflux for 1 hour 30 minutes and then the excess hydrazine hydrate is evaporated in vacuo; the solution is then cooled and diluted with distilled water, and the neutral products are extracted with chloroform.
- Example 11(b) following the procedure of Example 11(b) but starting from 110 g of ethyl [2-methyl-indanyl-(5)]-glyoxylate, 98 g of [2-methyl-indanyl-(5)]-glyoxylic acid are obtained and are used in crude form for the remainder of the operations.
- Example 11(a) following the procedure of Example 11(a) but using 68 g of 2,2-dimethyl-indane and 73.5 g of ethyloxalyl chloride, 110 g of ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
- Example 11(b) following the procedure of Example 11(b) but starting from 110 g of ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate, 92 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid are obtained and are used in crude form for the remainder of the operations.
- the Grignard reagent prepared from 42.3 g of magnesium and 135 ml of methyl iodide in 850 ml of anhydrous ether is added dropwise to a solution, cooled in ice, of 100 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid in 850 ml of anhydrous ether. The addition lasts for 1 hour.
- the reaction mixture is then stirred at the temperature of the laboratory for 2 hours and is then poured onto kg (sic) of ice and acidified by means of 10% strength hydrochloric acid.
- the mixture is extracted with ethyl acetate which is washed with water and dried. After evaporation of the solvent and washing the crystals obtained with petroleum ether, 80.2 g of 2-hydroxy-2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
- Example 14(a) following the procedure of Example 14(a) but starting from 63 g of [2-methyl-indanyl-(5)]-glyoxylic acid, 48 g of 2-hydroxy-2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
- Example 14(a) following the procedure of Example 14(a) but starting from 62 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid, 37.3 g of 2-hydroxy-2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
- Example 14(a) following the procedure of Example 14(a) but starting from 64.5 g of [2-isopropyl-indanyl-(5)]-glyoxylic acid (described above) and 207 g of ethyl bromide, 70.9 g of 2-hydroxy-2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
- Example 14(b) following the procedure of Example 14(b) but starting from 70.9 g of 2-hydroxy-2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid, 60.7 g of 2-ethylene-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
- Example 11(a) following the procedure of Example 11(a) but using 77 g of 2-ethyl-indane and 83 g of ethyloxalyl chloride, 116.3 g of ethyl [2-ethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
- Example 14(a) following the procedure of Example 14(a) but starting from 93.6 g of [2-ethyl-indanyl-(5)]-glyoxylic acid, 100 g of 2-hydroxy-2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained and are used in crude form for the remainder of the operations.
- Example 14(b) following the procedure of Example 14(b) but starting from 100 g of 2-hydroxy-2-methyl-[2-ethyl-indanyl-(5)]-acetic acid, 77.5 g of 2-methylene-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of crystals.
- dimethylaminoethanol 4.5 g of dimethylaminoethanol are added to 11.6 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, melting point 81°-83° C (described above), dissolved in 50 ml of ether. The solution is concentrated in vacuo and the residue is dilted with 50 ml of pentane. 9.8 of the dimethylaminoethanol salt of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are precipitated under cold conditions in the form of white crystals.
- Example 19 following the procedure of Example 19 but starting from 13.5 g of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid and 4.9 g of dimethylaminoethanol, 11.2 g of the dimethylaminoethanol salt of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
- Boiling point 12 mm Hg 148°-151° C.
- Example 21(b) following the procedure of Example 21(b) but starting from 7 g of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid chloride, 6.8 g of the morpholino-ethyl ester of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of an oil. On adding 2.7 g of oxalic acid dissolved in ethanol, 7.1 g of the oxalate of the morpholino-ethyl ester of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from isopropanol.
- Boiling point 10 mm Hg 140°-145° C.
- Example 21(b) following the procedure of Example 21(b) but starting from 10.5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid chloride, there are obtained, after having taken up the residue obtained in a mixture of acetone and ether and after having added a solution of hydrogen chloride in ether thereto, 12 g of the hydrochloride of the morpholino-ethyl ester of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid in the form of white crystals.
- Example 21(b) following the procedure of Example 21(b) but starting from 10.2 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid chloride, there are obtained, after having diluted the residue obtained with a mixture of acetone and ether and after having added a solution of hydrogen chloride in ether thereto, 8.9 g of the hydrochloride of the morpholino-ethyl ester of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid in the form of white crystals.
- Boiling point 10 mm Hg 170°-175° C.
- Example 21(b) following the procedure of Example 21(b) but starting from 16.5 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid chloride, 15 g of the morpholino-ethyl ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of an oil. On adding 5.5 g of oxalic acid dissolved in ethanol, 15.5 g of the oxalate of the morpholino-ethyl ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from ethanol.
- Boiling point 1 mm Hg 150° C.
- Example 21(b) following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 4.1 g of diethylaminoethanol, 10 g of the diethylaminoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained, after evaporation of the organic solvents in vacuo; 3.8 g of oxalic acid dissolved in ethanol are added to the above ester to yield, after recrystallisation from isopropanol, 11 g of the oxalate of the diethylaminoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals.
- Example 21(b) following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 4.1 g of dimethylamino- ⁇ -dimethyl-ethanol, 11 g of the dimethylamino- ⁇ -dimethyl-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained; 3.8 g of maleic acid dissolved in acetone are added to the above ester to yield 11.2 g of the maleate of the dimethylamino- ⁇ -dimethylethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals.
- Example 21(b) following the procedure of Example 21(b) but using 14 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 7.2 g of piperidinoethanol, 15 g of ester are obtained; 5.5 g of oxalic acid dissolved in ethanol are added to the above ester to yield 14 g of the oxalate of the piperidinoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals, after recrystallisation from ethanol.
- Boiling point 1 mm Hg 130°-132° C.
- Boiling point 0 .5 mm Hg 115° C.
- a mixture of 100 g of [2-isopropyl-indanyl-(5)]-methyl ketone, 22.2 g of sulphur and 75 g of morpholine is heated at 140° C for 12 hours. Thereafter, the reaction mixture is concentrated in vacuo and is then taken up in 200 ml of 95° strength ethanol. The crystals formed are filtered off and washed with a small amount of cold 95° strength ethanol. 95 g of [2-isopropyl-indanyl-(5)]-acetic acid morpholinethioamide are thus obtained in the form of light yellow crystals.
- the products to be tested are administered orally to batches of 12 SPF male rats, OFA strain, weighing 120-130 g, 2 hours and 30 minutes (1/2 dose each time) before the subcutaneous plantar injection of 0.05 ml of a 1% strength solution of carraghenine.
- the volume of the back paw which received the phlogogenic agent is measured at regular intervals.
- the 50% effective dose is calculated at the moment of greatest swelling of the controls.
- the products tested are administered orally to batches of 6 male mice (SPF 1 , OF 1 strain) weighing 19-20 g.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to certain indane derivatives of general formula <IMAGE> (I) in which:
Description
This is a division, of applicaton Ser. No. 546,095, filed Jan. 31. 1975.
The present invention relates to certain indane derivatives, to processes for their preparation and to their use in therapy.
The present invention provides a compound of general formula: ##STR2## in which:
X represents a hydrogen or halogen atom; R1 and R2, which may be identical or different, each represents a hydrogen atom an alkyl group containing 1 to 5 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms; R3 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; and Y represents --CH2 OH or a group of formula --COOR4 in which R4 represents a hydrogen atom, 1/v (M) where M is a metal of valency v, or a group of formula:
--(CH.sub.2).sub.n --NR.sub.5 R.sub.6
wherein n is an integer of 1 to 5 and R5 and R6, which may be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms, an aryl group or an aralkyl group, or R5 and R6, together with the nitrogen atom to which they are bonded, form an N-heterocyclic group with 5 to 7 ring members, which heterocyclic group optionally contains a second heteroatom (e.g. a nitrogen, oxygen or sulphur atom) and/or one or more substituents (e.g. alkyl groups containing 1 to 5 carbon atoms), or a pharmaceutically acceptable addition salt of a compound of formula (I).
The aforesaid alkyl groups of 1 to 5 carbon atoms may be straight or branched; similary, the group --CH2)n may be straight or branched. The cycloalkyl groups of 3 to 7 carbon atoms may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, cyclohexyl being preferred. The substituents R1 and R2 may be on the same or different carbon atoms of the indane nucleus.
The metal M is preferably from group I, II or III of the periodic classification; sodium, potassium, calcium and aluminium are especially suitable.
Suitable N-heterocyclic groups --NR5 R6 include, more especially, pyrrolidino, morpholino, thiomorpholino, 3,5-dimethyl-morpholino, piperidino, 4'-methyl-piperidino, piperazino, 4-(β-hydroxyethyl)-piperazino, 4-p-chlorophenyl-piperazino and azepino.
When R4 is an aryl group, it may be, for example, phenyl, and when it is aralkyl, it may be, e.g. α-phenylethyl, β-phenylethyl, or benzyl.
The invention includes the addition salts of the compounds of the formula I, especially the addition salts with amines when R4 is hydrogen and the addition salts with acids or quaternary ammonium salts when R4 is --(CH2)n NR5 R6. The addition salts with acids may be produced by reaction of the base with an inorganic or organic acid in manner known per se. Suitable acids for this purpose are, more especially, hydrochloric, sulphuric, phosphoric, oxalic, succinic, methanesulphonic, cyclohexylsulphamic, formic, aspartic, glutamic, N-acetyl-aspartic, N-acetyl-glutamic, ascorbic, maleic, malic, fumaric, lactic, benzoic, cinnamic and p-toluenesulphonic acids.
Particularly preferred compounds of formula (I) are those in which R1 and R2 each represents a hydrogen-atom or a methyl, ethyl isopropyl or cyclohexyl group, R3 represents a hydrogen atom or a methyl or ethyl group and X represents a hydrogen atom. If Y represents a group of formula --COOR4, R4 is preferably a hydrogen atom or a group of formula ##STR3##
The compounds of formula (I) can be prepared by conventional techniques. In many cases an indane of the formula: ##STR4## in which R1, R2 and X are as hereinbefore defined, is a convenient starting material. Typical processes which can be used are the following:
A. A process which comprises:
a. reacting a compound of the formula ##STR5## in which R1, R2 and X are as hereinbefore defined with an ethyloxalyl halide and hydrolysing the resulting keto-ester of formula: ##STR6## under acidic or basic conditions to obtain a keto-acid of the formula: ##STR7## and either:
b. subjection the keto-acid of formula (VI) to a Wolff-Kishner reduction to obtain a compound of formula (I) in which Y represents a --COOH group and R3 represents a hydrogen atom, or
c. reacting the keto-acid of formula (VI) with an organo-magnesium compound of the formula R3 MgZ in which Z is a halogen atom and R3 is an alkyl group containing 1 to 5 carbon atoms to obtain a compound of formula: ##STR8## dehydrating the compound of formula (VII) to obtain a compound of formula: ##STR9## in which R'3 represents a group of formula --(CH2)x-1 H where x is the number of carbon atoms in R3, and hydrogenating the compound of formula (VIII) to obtain a compound of formula (I) in which Y represents a --COOH group and R3 represents an alkyl group containing 1 to 5 carbon atoms; and if desired, converting the compound of formula (I) obtained in step (b) or (c) into a pharmaceutically acceptable addition salt thereof.
The preferred ethyloxalyl halide for use in step a) is the chloride and the preferred compounds of formula R3 MgZ for use in step (c) are those in which Z is iodine. The various steps of process A may be carried out using methods known in the art; for example step (a) may be carried out under typical Friedel-Crafts' reaction conditions in the presence of a Lewis acid such as AlCl3 and a solvent such as ethylene chloride and step (b) may be carried out using hydrazine in a solution containing sodium or potassium ions. The Grignard reaction in step (c) is suitably carried out in an ether solvent, the dehydration of the compound of formula VII may be carried out using a strong acid such as concentrated sulphuric acid and the final hydrogenation is suitably carried out in the presence of a catalyst, for example Raney nickel. Process (A) is illustrated by the following reaction scheme: ##STR10##
B. Processes for the preparation of compounds of formula (I) in which Y represents a --COOH group, which processes include the step of hydrolysing a nitrile of general formula: ##STR11## in which R1, R2, R3 and X are as hereinbefore defined under acidic or basic conditions, and, if desired converting the resulting compound of formula (I) into a pharmaceutically acceptable addition salt thereof.
A nitrile of formula (IVa) in which R3 represents an alkyl group containing 1 to 5 carbon atoms can be obtained by reacting a nitrile of formula (IVa) in which R3 represents a hydrogen atom with a metallating agent such as sodium or potassium hydride or amide or potassium tert-butylate and reacting the resulting compound of formula: ##STR12## in which M is an alkali metal atom, with a halide of formula R3 Z in which R3 represents an alkyl group containing 1 to 5 carbon atoms and Z is a halogen atom, preferably bromine or iodine.
Further processes of general type (B) are the following processes (C) and (D).
C. A process which comprises
a. chloromethylating in known manner a compound of the formula: ##STR13## in which R1, R2 and X are as hereinbefore defined to obtain a compound of formula: ##STR14##
b. reacting the compound of formula (III) with an alkali metal cyanide to obtain a compound of formula: ##STR15## and
c. hydrolysing the compound of formula (IV) under acidic or basic conditions to obtain a compound of formula (I) in which Y represents a --COOH group and R3 represents a hydrogen atom, and, if desired, converting the compound of formula (I) into a pharmaceutically acceptable addition salt thereof.
Step (a) is preferably carried out using hydrochloric acid and formaldehyde or trioxymethylene.
Process (C) is illustrated by the following reaction scheme: ##STR16##
D. A process which comprises
a. reacting a compound of the formula: ##STR17## in which R1 and R2 are as defined in claim 1 in known manner with a halide or anhydride of an acid of formula R3 --COOH in which R3 represents an alkyl group containing 1 to 5 carbon atoms, to obtain a ketone of formula: ##STR18## in which R1, R2 and R3 are as hereinbefore defined.
b. reducing the ketone of formula (XIII) in known manner to obtain an alcohol of formula: ##STR19##
c. converting the alcohol of formula (XIV) in known manner into a halide of formula: ##STR20## in which Q is chlorine or bromine.
d. reacting the halide of formula (XV) with an alkali metal cyanide to obtain a compound of formula: ##STR21## and
e. hydrolysing the compound of formula (IVa) under acidic or basic conditions to obtain a compound of formula (I) in which X represents a hydrogen atom, R3 represents an alkyl group containing 1 to 5 carbon atoms and Y represents a --COOH group, and if desired, converting the compound of formula (I) into a pharmaceutically acceptable addition salt thereof.
The various steps of process (D) may be carried out using method known in the art; step (a) may be carried out under typical Friedel-Crafts' reaction conditions, step (b) may be carried out using conventional reducing agents suitable for reducing a ketone to an alcohol, for example an alkali metal borohydride or lithium aluminium hydride, and step (c) may be carried out using, for example, phosphorus tribromide or thionyl chloride.
Process (D) is illustrated by the following reaction scheme: ##STR22##
Another process which may be used to prepare compounds of formula (I) in which R3 represents a hydrogen atom and Y represents a --COOH group is the following:
E. A process which comprises reacting a compound of the formula: ##STR23## in which R1, R2 and X are as hereinbefore defined in known manner with sulphur and a primary or secondary amine of formula NHR5 R6 wherein R5 and R6 are as hereinbefore defined with the proviso that at least one of R5 and R6 is other than hydrogen, to obtain a thioamide of the formula: ##STR24## in which R1, R2, R5, R6 and X are as hereinbefore defined, and hydrolysing the thioamide of formula (XI) to obtain a compound of formula (I) in which R3 represents a hydrogen atom and Y represents a --COOH group, and, if desired, converting the compound of formula (I) into a pharmaceutically acceptable addition salt thereof.
This process involves a Willgerodt reaction (a variation of the Kindler reaction). The ketones of formula (X) in which X represents a hydrogen atom can be obtained by step (a) of process (D). The hydrolysis of the thioamide is preferably carried out under acid conditions.
The compounds of formula (I) in which Y represents a --CH2 OH group can be prepared by methods including the step of reducing a compound of formula: ##STR25## in which R1, R2, R3 and X are as hereinbefore defined and R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms. The compounds of formula (XVI) in which R is hydrogen can be prepared by any of the processes (A) to (E) described above and the compounds in which R is an alkyl group can be obtained by conventional esterification of the corresponding acid. The reduction can be carried out by means of a reducing agent, for example, lithium aluminium hydride, in an organic solvent such as ether or tetrahydrofuran.
The compounds of formula (I) in which Y represents a group of formula --COOR4 in which R4 represents a group of formula --(CH2)n --NR5 R6 can be prepared by a process of the following type:
F. A process which comprises either
a. reacting the halide of an acid of formula: ##STR26## in which R1, R2, R3 and X are as hereinbefore defined with an aminoalcohol of the formula: ##STR27## in which n, R5 and R6 are as hereinbefore defined or
b. reacting a salt of an acid of formula (Ia) wit a halide of the formula: ##STR28## in which n, R5 and R6 are as hereinbefore defined and Z is a halogen atom.
Process (F) is illustrated by the following reaction scheme: ##STR29##
The compounds of the invention and their nontoxic addition salts possess valuable pharmacological activities and are useful in therapy, especially as analgesic and anti-inflammatory agents. They can, for example, be used as anti-inflammatory agents for counteracting rheumatism.
The invention therefore also provides therapeutic compositions which are especially useful in the treatment of inflammations and algias, rheumatisms and pain syndromes which compositions comprise a pharmaceutically effective amount of at least one compound of formula (I) or one of its non-toxic addition salts and a pharmaceutically acceptable carrier or diluent.
The compounds of formula (I) can, for example, be administered to man in the form of gelatine-coated pills containing 50 to 250 mg of active principle at a dose of 2 to 6 gelatine-coated pills per day, in the form of suppositories containing 100 to 500 mg of active principle at a daily dose of 2 to 5 suppositories per day, in the form of a potable suspension containing 25 mg of active principle per 5 cm3 at a daily dose of 10 to 40 cm3 or in the form of an injectable solution containing 50 mg of active principle per 2 ml of solution at a daily dose of 2 to 4 injections.
The compounds of formula (I) possess an LD50 in rats of approximately 250 mg/kg when administered orally, have little tendency to cause ulcers, and possess an activity to toxicity ratio which is generally higher than that of the known products possessing similar pharmacological properties.
The invention is illustrated by the following Examples. Examples 2 to 7 and 11 to 18 illustrate process A), Example 1 illustrates process C), Example 26 illustrates process D), Example 36 illustrates process E) and Examples 8, 9 and 21 to 32 illustrate process F). Examples 33 to 35 and 37 illustrate the preparation of compounds in which Y is --CH2 OH and Examples 19 and 20 illustrate the preparation of addition salts.
Formula III
r.sub.1 = r.sub.2 = ch.sub.3 x = h
a mixture of 73 g of 1,3-dimethyl-indane, 28 g of trioxymethylene, 64 ml of acetic acid, 41 ml of 85% strength phosphoric acid and 100 ml of concentrated hydrochloric acid is stirred for 24 hours at between 58° and 60° C. The reaction mixture is taken up in a mixture of water and ice and the organic products are extracted with ether. The ether phase is washed with water and dried over sodium sulphate. After evaporation of the ether, the residue obtained is distilled in vacuo. 44.8 g of 1,3-dimethyl-5-chloromethyl-indane are thus obtained in the form of a colourless liquid. Boiling point 1 mm Hg = 110° C.
Formula IV
r.sub.1 = r.sub.2 = ch.sub.3 x = h
a solution of 25 g of potassium cyanide in 30 ml of water is added over the course of 1 hour to a solution of 44.8 g of 1,3-dimethyl-5-chloromethyl-indane in 130 ml of ethanol. The reaction mixture is heated under reflux for 4 hours and is then cooled, diluted with a mixture of water and ice and extracted with ether. The ether phase is washed carefully with water and dried over sodium sulphate. After evaporation of the ether, the residue obtained is distilled in vacuo. 31.8 g of [1,3-dimethyl-indanyl-(5)]-acetonitrile are thus obtained in the form of a colourless liquid. Boiling point 0.7 mm Hg = 125°-132° C.
Formula I
r.sub.1 = r.sub.2 = ch.sub.3 r.sub.3 = r.sub.4 = x = h
a solution of 31.8 g of [1,3-dimethyl-indanyl-(5)]-acetonitrile in 175 ml of ethanol containing a solution of 62 g of potassium hydroxide in 100 ml of water is heated under reflux for 16 hours.
After evaporation of the ethanol in vacuo, the reaction mixture is diluted with 200 ml of water and then filtered. The filtrate is acidified at 0° by means of 10% strength hydrochloric acid and the precipitate formed is filtered off, washed with water and dried. After recrystallisation from toluene, 20 g of [1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point = 116°-117° C.
Formula V
r.sub.1 = r.sub.2 = ch.sub.3 x = h
a solution of 78 g of 1,3-dimethyl-indane and 83.5 g of ethyloxalyl chloride in 300 ml of methylene chloride is added, over the course of 1 hour, to a stirred suspension of 125 g of aluminum chloride in 300 ml of methylene chloride, whilst cooling in such a way that the temperature of the reaction mixture remains below 5°. The mixture is then stirred for 2 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified to pH 3 by means of hydrochloric acid. The methylene chloride phase is isolated and the mother liquors are extracted with methylene chloride. The methylene chloride phases are combined, washed with water saturated with sodium chloride and dried over sodium sulphate. After evaporation of the solvent, 119 g of ethyl [1,3-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
r.sub.1 = r.sub.2 = ch.sub.3 x = h
a solution of 119 g of ethyl [1,3-dimethyl-indanyl-(5)]-glyoxylate in 600 ml of ethanol is treated with a solution of 20.5 g of sodium hydroxide in 600 ml of water and is heated under reflux for 2 hours. The mixture is then cooled, diluted with 300 ml of water and acidified at 0° by means of 10% strength hydrochloric acid. The mixture is extracted with chloroform which is then washed with water saturated with sodium chloride, dried over sodium sulphate and evaporated. After vacuum distillation of the residue obtained, 77 g of [1,3-dimethyl-indanyl-(5)]-glyoxylic acid are isolated. Boiling point 1.5 mm Hg = 170° C.
Formula I
r.sub.1 = r.sub.2 = ch.sub.3 r.sub.3 = r.sub.4 = x = h
a mixture of 12 g of [1,3-dimethyl-indanyl-(5)]-glyoxylic acid and 25 ml of hydrazine hydrate is heated under reflux for 30 minutes. The mixture is cooled to 70° C and 15 g of potassium hydroxide pellets are added in small portions. After the end of the addition, the mixture is heated under reflux for 1 hour 30 minutes and then the excess hydrazine hydrate is evaporated in vacuo. The solution is then cooled and acidified at 0° C by means of 10% strength hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried. After recrystallisation from toluene, 7.7 g [1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals. Melting point 116°-117° C.
Formula V
r.sub.1 = r.sub.2 = ch.sub.3 x = cl
Following the procedure of Example 2(a) but using 50 g of 1,3-dimethyl-6-chloro-indane and 43 g of ethyloxalyl chloride, 80 g of ethyl [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
r.sub.1 = r.sub.2 = ch.sub.3 x = cl
Following the procedure of Example 2(b) but starting from 80 g of ethyl [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylate, 61 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylic acid are obtained in the form of pale yellow crystals. Melting point 170°-173° C.
Formula I
r.sub.1 = r.sub.2 = ch.sub.3 x = cl
R.sub.3 = R.sub.4 = H
following the procedure of Example 2(c) but starting from 20 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylic acid, 10.5 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from toluene. Melting point 158°-160° C.
Formula V
r.sub.1 = x = h r.sub.2 = isopropyl
Following the procedure of Example 2(a) but using 43 g of 2-isopropyl-indane and 42.2 g of ethyloxyalyl chloride, 69 g of ethyl [2-isopropyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
r.sub.1 = x = h r.sub.2 = isopropyl
Following the procedure of Example 2(b) but starting from 69 g of ethyl [2-isopropyl-indanyl-(5)]-glyoxylate, 58 g of 2-[2-isopropyl-indanyl-(5)]-glyoxylic acid are obtained in the form of pale yellow crystals, recrystallised from a 50/50 mixture of hexane and cyclohexane. Melting point 55°-60° C.
Formula I
r.sub.1 = x = r.sub.3 = r.sub.4 = h
r.sub.2 = isopropyl
Following the procedure of Example 2(c) but starting from 20 g of [2-isopropyl-indanyl-(5)]-glyoxylic acid, 11 g of [2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from hexane. Melting point 80°-81° C.
Formula V
r.sub.2 = x = h r.sub.1 = cyclohexyl
Following the procedure of Example 2(a) but using 70 g of 1-cyclohexyl-indane and 54.6 g of ethyloxalyl chloride, 110 g of ethyl [1-cyclohexyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
r.sub.2 = x = h r.sub.1 = cyclohexyl
Following the procedure of Example 2(b) but starting from 110 g of ethyl [1-cyclohexyl-indanyl-(5)]-glyoxylate, 90 g of [1-cyclohexyl-indanyl-(5)]-glyoxylic acid are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula I
r.sub.2 = x = r.sub.3 = r.sub.4 = h
r.sub.1 = cyclohexyl
Following the procedure of Example 2(c) but starting from 30 g of [1-cyclohexyl-indanyl-(5)]-glyoxylic acid, 15.9 g of [1-cyclohexyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from pentane. Melting point 75°-78° C.
Formula VII
r.sub.1 = r.sub.2 = ch.sub.3 x = h
the Grignard reagent, prepared from 34.2 g of magnesium in 75 ml of ether and 105 ml of methyl iodide in 200 ml of ether, is added dropwise to a solution, cooled in ice, of 65.5 g of [1,3-dimethyl-indanyl-(5)]-glyoxylic acid in 900 ml of ether. The addition lasts for 1 hour. The reaction mixture is then stirred at the temperature of the laboratory for 2 hours and is then poured onto 2 kg of ice and acidified by means of 10% strength hydrochloric acid. The mixture is extracted with ethyl acetate and the extract is washed with water and dried. After evaporation of the solvent, 53 g of 2-hydroxy-2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid are obtained and are used in crude form for the remainder of the operations.
Formula VIII
r.sub.1 = r.sub.2 = ch.sub.3 x = h
a solution of 48 g of 2-hydroxy-2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid in 2.1 litres of dioxane and 105 ml of concentrated sulphuric acid is heated under reflux for 2 hours and is then cooled and poured onto 2 kg of ice and extracted with chloroform.
The extracts are washed with water and dried over sodium sulphate. After evaporation of the solvent, 42 g of 2-methylene-[1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 66°-69° C after recrystallisation from pentane.
Formula I
r.sub.1 = r.sub.2 = r.sub.3 = ch.sub.3
x = h r.sub.4 = na
35.5 g of 2-methylene-[1,3-dimethyl-indanyl-(5)]-acetic acid dissolved in 350 ml of methanol are hydrogenated in the presence of 10 g of Raney nickel at 80° C under 40 kg for 7 hours. After cooling, filtration and evaporation of the filtrate, a thick white oil is obtained which does not crystallise. 21.4 g of this oil are treated with a solution of 20 ml of sodium ethylate prepared from 2 g of sodium dissolved in 20 ml of ethanol. After evaporation of the solvent, the residue is taken up in ether and 16 g of the sodium salt of 2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of a white powder which is soluble in water.
Analysis: potentiometric determination (perchloric acid)
Molecular weight found: 239.6
Molecular weight calculated: 240
Formula VII
r.sub.1 = x = h
r.sub.2 = isopropyl
Following the procedure of Example 6(a) but starting from 44 g of [2-isopropyl-indanyl-(5)]-glyoxylic acid, 39 g of 2-hydroxy-2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from isopropanol.
Melting point 140°-143° C.
Formula VIII
r.sub.1 = x = h
r.sub.2 = isopropyl
Following the procedure of Example 6(b) but using 21.8 g of 2-hydroxy-2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, 19 g of 2-methylene-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 145°-148° C.
Formula I
r.sub.1 = x = r.sub.4 = h
r.sub.2 = isopropyl R.sub.3 = CH.sub.3
a solution of 19 g of 2-methylene-[2-isopropyl-indanyl-(5)]-acetic acid in 250 ml of dioxane containing 1.5 g of 5% strength Pd/C is hydrogenated under a pressure of 50 kg for 4 hours. The catalyst is filtered off and the filtrate is concentrated in vacuo. 15 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are thus obtained in the form of white crystals, after recrystallisation from pentane.
Melting point 81°-83° C.
Formula IX
r.sub.1 = r.sub.3 = x = h
r.sub.2 = isopropyl
A solution of 9 g of [2-isopropyl-indanyl-(5)]-acetic acid and 6 g of thionyl chloride in 50 ml of benzene is heated at 80° C for 2 hours. The solvent and the excess thionyl chloride are then evaporated in vacuo. The oil obtained is used in crude form for the remainder of the operations.
Formula I
r.sub.1 = r.sub.3 = x = h
r.sub.2 = isopropyl ##STR30##
6 g of morpholino-ethanol are added dropwise at 0° C to a solution of [2-isopropyl-indanyl-(5)]-acetic acid chloride, prepared from 9 g of acid, in 100 ml of ether. The mixture is stirred for 1 hour at ambient temperature and is then taken up in 100 ml of water containing 5% of hydrochloric acid. The aqueous phase is isolated and rendered alkaline at 0° C by means of a 5% strength solution of sodium hydroxide, and the organic products are extracted with ether. The ether extracts are washed with water and dried over sodium carbonate. After evaporation of the ether, 7 g of the morpholino-ethyl ester of [2-isopropyl-indanyl-(5)]-acetic acid are obtained. On adding a solution of hydrogen chloride in ether and recrystallising from acetone, 7 g of the hydrochloride are obtained in the form of white crystals.
Melting point 153°-156° C.
Formula IX
r.sub.1 = x = h
r.sub.2 = isopropyl R.sub.3 = CH.sub.3
following the procedure of Example 8(a), 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride is prepared from 10 g of acid.
Formula I
r.sub.1 = x = h
r.sub.2 = isopropyl
R.sub.3 = CH.sub.3 ##STR31##
following the procedure of Example 8(b) but using 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride prepared from 10 g of acid, 7 g of the morpholino-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained. After adding 2.55 g of oxalic acid in acetone and recrystallising from acetone, 7.3 g of the oxalate are obtained in the form of white crystals.
Melting point 135°-140° C.
A solution of 100 g of 2-isopropyl-indane and 65 ml of acetic anhydride in 400 ml of methylene chloride is added over the course of 1 hour to a stirred suspension of 190 g of aluminium chloride in 400 ml of methylene chloride, whilst cooling in such a way that the temperature of the reaction mixture remains below 10° C. The mixture is then stirred for 5 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified to pH 3 by means of hydrochloric acid. The methylene chloride phase is isolated and the mother liquors are extracted with methylene chloride. The methylene chloride phases are combined, washed with water and dried over sodium sulphate. After evaporation of the solvent, the residue, weighing 137 g, is distilled in vacuo; 105.5 g of [2-isopropyl-indanyl-(5)]-methyl ketone are thus obtained in the form of white crystals which melt at a very low temperature (< 40° C).
Boiling point1.5 mm Hg = 121°-125° C.
70 ml of thionyl chloride are added over the course of 2 hours to a solution of 106 g of α-[2-isopropyl-indanyl-(5)]-ethanol in 500 ml of benzene, whilst stirring magnetically. After stirring for 15 minutes at ambient temperature, the reaction mixture is poured onto ice. The benzene phase is isolated and the mother liquors are extracted with ether. The combined organic phases are washed with water, with a 5% strength bicarbonate solution and then again with water and are finally dried over sodium sulphate. After the organic solvents have been evaporated in vacuo, the residue obtained is distilled in vacuo. 104.1 g of α-[2-isopropyl-indanyl-(5)]-ethyl chloride are thus isolated in the form of an oil.
Boiling point1.5 mm Hg = 132°-136° C.
A solution of 104.1 g of α-[2-isopropyl-indanyl-(5)]-ethyl chloride in 70 ml of dimethylsulphoxide is added dropwise to a solution of 24.3 g of sodium cyanide in 210 ml of dimethylsulphoxide. After the end of the addition, the reaction mixture is heated at 70°-80° C for 4 hours 30 minutes. The reaction mixture is then cooled, taken up in a mixture of water and ice and extracted with ether. The ether extracts are washed carefully with water and dried over sodium sulphate. After evaporation of the ether, the residue is distilled in vacuo; 74.1 g of [2-isopropyl-indanyl-(5)]-2-methyl-acetonitrile are thus obtained in the form of an oil.
Boiling point1.5 mm Hg = 135°-150° C.
A solution of 74.1 g of [2-isopropyl-indanyl-(5)]-2-methyl-acetonitrile in 185 ml of ethanol containing 185 ml of water and 74 g of potassium hydroxide is heated under reflux for 12 hours.
Ice and water are added to the reaction mixture and the neutral products are extracted with ether.
After acidifying the cold mother liquors, the acid is extracted with ether. The ether phase is washed with water and dried over sodium sulphate.
After evaporation of the ether and recrystallisation (of the residue) from petroleum ether, 50.6 g of 2-methyl[-2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 81°-83° C.
Formula V
r.sub.1 = x = h r.sub.2 = cyclohexyl
A solution of 110.3 g of 2-cyclohexyl-indane and 86 g of ethyloxalyl chloride in 400 ml of methylene chloride is added over the course of 1 hour to a stirred suspension of 128 g of aluminium chloride in 400 ml of methylene chloride, whilst cooling in such a way that the temperature of the reaction mixture remains below 5° C. The mixture is then stirred for 2 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified to pH 3 by means of hydrochloric acid. The methylene chloride phase is isolated and the mother liquors are extracted with methylene chloride. The methylene chloride phases are combined, washed with water saturated with sodium chloride and dried over sodium sulphate.
After evaporation of the solvent, 156,3 g of ethyl [2-cyclohexyl-indanyl-(5)]-glyoxylate are obtained and are used in crude form for the remainder of the operations.
Formula VI
r.sub.1 = x = h r.sub.2 = cyclohexyl
A solution of 156.3 g of ethyl [2-cyclohexyl-indanyl-(5)]-glyoxylate in 700 ml of ethanol, which has been treated with a solution of 30 g of sodium hydroxide in 700 ml of water, is heated under reflux for 2 hours. The mixture is then cooled, diluted with 350 ml of water and acidified at 0° C by means of 10% strength hydrochloric acid. The mixture is extracted with ether which is washed with water, dried over sodium sulphate and evaporated. 136 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid are thus obtained in the form of pale yellow crystals, after washing with a mixture of pentane and petroleum ether.
Melting point 117°-121° C.
Formula I
r.sub.1 = r.sub.3 = x = h
r.sub.2 = cyclohexyl
A mixture of 40 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid and 100 ml of hydrazine hydrate is heated under reflux for 45 minutes. The mixture is cooled to 70° C and 50 g of potassium hydroxide pellets are added in small portions. After the end of the addition, the mixture is heated under reflux for 1 hour 30 minutes and then the excess hydrazine hydrate is evaporated in vacuo; the solution is then cooled and diluted with distilled water, and the neutral products are extracted with chloroform.
The mother liquors are acidified at 0° C by means of 10% strength hydrochloric acid and the acid is extracted with ether which is washed with water, dried and evaporated. After recrystallisation from a 50/50 mixture of cyclohexane and hexane, 29 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid are obtained in the form of white crystals.
Melting point 126°-132° C.
Formula V
r.sub.1 = x = h r.sub.2 = methyl
Following the procedure of Example 11(a) but using 66 g of 2-methyl-indane and 78.5 g of ethyloxalyl chloride, 110 g of ethyl [2-methyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
r.sub.1 = x = h r.sub.2 = ch.sub.3
following the procedure of Example 11(b) but starting from 110 g of ethyl [2-methyl-indanyl-(5)]-glyoxylate, 98 g of [2-methyl-indanyl-(5)]-glyoxylic acid are obtained and are used in crude form for the remainder of the operations.
Formula I
r.sub.1 = r.sub.3 = x = h r.sub.2 = ch.sub.3
following the procedure of Example 11(c) but starting from 40 g of [2-methyl-indanyl-(5)]-glyoxylic acid, 26 g of [2-methyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from pentane.
Melting point 57°-58° C.
Formula V
x = h r.sub.1 = r.sub.2 = ch.sub.3
following the procedure of Example 11(a) but using 68 g of 2,2-dimethyl-indane and 73.5 g of ethyloxalyl chloride, 110 g of ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
x = h r.sub.1 = r.sub.2 = ch.sub.3
following the procedure of Example 11(b) but starting from 110 g of ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate, 92 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid are obtained and are used in crude form for the remainder of the operations.
Formula I
r.sub.3 = x = h r.sub.1 = r.sub.2 = ch.sub.3
following the procedure of Example 11(c) but starting from 35 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid, 24.7 g of [2,2-dimethyl-indanyl-(5)]acetic acid are obtained in the form of white crystals, after recrystallisation from pentane.
Melting point < 40° C.
Formula VII
r.sub.1 = x = h r.sub.2 = cyclohexyl R.sub.3 = CH.sub.3
the Grignard reagent prepared from 42.3 g of magnesium and 135 ml of methyl iodide in 850 ml of anhydrous ether is added dropwise to a solution, cooled in ice, of 100 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid in 850 ml of anhydrous ether. The addition lasts for 1 hour. The reaction mixture is then stirred at the temperature of the laboratory for 2 hours and is then poured onto kg (sic) of ice and acidified by means of 10% strength hydrochloric acid. The mixture is extracted with ethyl acetate which is washed with water and dried. After evaporation of the solvent and washing the crystals obtained with petroleum ether, 80.2 g of 2-hydroxy-2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 142°-144° C.
Formula VIII
r.sub.1 = x = h r.sub.2 = cyclohexyl
R'.sub.3 = H
a solution of 80.2 g of 2-hydroxy-2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid in 1.950 l of dioxane and 106 ml of concentrated sulphuric acid is heated under reflux for 2 hours and is then cooled and poured onto 2 kg of ice. The precipitate obtained is washed with water and dried. 72 g of 2-methylene-[2-cyclohexyl-indanyl-(5)]-acetic acid are thus obtained in the form of light beige crystals.
Melting point 179°-182° C.
Formula I
r.sub.1 = x = h r.sub.2 = cyclohexyl
R.sub.3 = CH.sub.3
72 g of 2-methylene-[2-cyclohexyl-indanyl-(5)]-acetic acid dissolved in 600 ml of dioxane are hydrogenated in the presence of 10 g of Raney nickel at 80° C under 50 kg for 7 hours. After cooling, filtration and evaporation of the filtrate, the crystals obtained are recrystallised from a 10/90 mixture of toluene and petroleum ether; 48 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid are thus obtained in the form of white crystals.
Melting point 119°-121° C.
Formula VII
r.sub.1 = x = h r.sub.2 = r.sub.3 = ch.sub.3
following the procedure of Example 14(a) but starting from 63 g of [2-methyl-indanyl-(5)]-glyoxylic acid, 48 g of 2-hydroxy-2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 97°-100° C.
Formula VIII
r.sub.1 = x = h r.sub.2 = ch.sub.3
r'.sub.3 = h
following the procedure of Example 14(b) but starting from 33 g of 2-hydroxy-2-methyl-[2-methyl-indanyl-(5)]-acetic acid, 29 g of 2-methylene-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 119° C.
Formula I
r.sub.1 = x = h r.sub.2 = r.sub.3 = ch.sub.3 r.sub.4 = na
29 g of 2-methylene-[2-methyl-indanyl-(5)]-acetic acid dissolved in 200 ml of methanol are hydrogenated in the presence of 10 g of Raney nickel at 80° C under 50 kg for 7 hours. After cooling, filtration and evaporation of the filtrate, an oil is obtained which does not crystallise. 14.6 g of this oil are treated with a solution of 20 ml of sodium ethylate prepared from 1.65 g of sodium dissolved in 20 ml of ethanol. After evaporation of the solvent, the residue is taken up in ether and 13 g of the sodium salt of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtainted in the form of a white powder which is soluble in water.
Melting point 127°-130° C.
Formula VII
x = h r.sub.1 = r.sub.2 = r.sub.3 = ch.sub.3
following the procedure of Example 14(a) but starting from 62 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid, 37.3 g of 2-hydroxy-2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 99°-103° C.
Formula VIII
x = h r.sub.1 = r.sub.2 = ch.sub.3 r'.sub.3 = h
following the method of Example 14(b) but starting from 37.3 g of 2-hydroxy-2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid, 30.7 g of 2-methylene-[2,2-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 115° C.
Formula I
x = h r.sub.1 = r.sub.2 = r.sub.3 = ch.sub.3
following the procedure of Example 15(c) but starting from 30.7 g of 2-methylene-[2,2-dimethyl-indanyl-(5)]-acetic acid, 22.5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from pentane.
Melting point 64°-65° C.
Formula VII
r.sub.1 = h r.sub.2 = isopropyl
R.sub.3 = C.sub.2 H.sub.5
following the procedure of Example 14(a) but starting from 64.5 g of [2-isopropyl-indanyl-(5)]-glyoxylic acid (described above) and 207 g of ethyl bromide, 70.9 g of 2-hydroxy-2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 113°-116° C.
Formula VIII
r.sub.1 = h r.sub.2 = isopropyl
R'.sub.3 = CH.sub.3
following the procedure of Example 14(b) but starting from 70.9 g of 2-hydroxy-2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid, 60.7 g of 2-ethylene-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 118°-123° C.
Formula I
r.sub.1 = x = h r.sub.2 = isopropyl
R.sub.3 = C.sub.2 H.sub.5
following the procedure of Example 15(c) but starting from 60.7 g of 2-ethylene-[2-isopropyl-indanyl-(5)]-acetic acid, 40 g of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from pentane.
Melting point 78°-80° C.
Formula V
r.sub.1 = x = h r.sub.2 = c.sub.2 h.sub.5
following the procedure of Example 11(a) but using 77 g of 2-ethyl-indane and 83 g of ethyloxalyl chloride, 116.3 g of ethyl [2-ethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula VI
r.sub.1 = x = h r.sub.2 = c.sub.2 h.sub.5
following the procedure of Example 11(b) but using 116.3 g of ethyl [2-ethyl-indanyl-(5)]-glyoxylate, 93.6 g of [2-ethyl-indanyl-(5)]-glyoxylic acid are obtained and are used in crude form for the remainder of the operations.
Formula VII
r.sub.1 = x = h r.sub.2 = c.sub.2 h.sub.5
r.sub.3 = ch.sub.3
following the procedure of Example 14(a) but starting from 93.6 g of [2-ethyl-indanyl-(5)]-glyoxylic acid, 100 g of 2-hydroxy-2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained and are used in crude form for the remainder of the operations.
Formula VIII
r.sub.1 = x = h r.sub.2 = c.sub.2 h.sub.5
r'.sub.3 = h
following the procedure of Example 14(b) but starting from 100 g of 2-hydroxy-2-methyl-[2-ethyl-indanyl-(5)]-acetic acid, 77.5 g of 2-methylene-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of crystals.
Melting point 88°-91° C.
Formula I
r.sub.1 = x = h r.sub.2 = c.sub.2 h.sub.5
r.sub.3 = ch.sub.3
following the procedure of Example 15(c) but starting from 77.5 g of 2-methylene-[2-ethyl-indanyl-(5)]-acetic acid, a residue weighing 79 g is obtained and is distilled in vacuo. 53.6 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are thus isolated and crystallise from pentane in the form of white crystals.
Melting point 44°-46° C.
Formula I
r.sub.1 = x = h r.sub.2 = isopropyl
R.sub.3 = CH.sub.3
4.5 g of dimethylaminoethanol are added to 11.6 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, melting point 81°-83° C (described above), dissolved in 50 ml of ether. The solution is concentrated in vacuo and the residue is dilted with 50 ml of pentane. 9.8 of the dimethylaminoethanol salt of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are precipitated under cold conditions in the form of white crystals.
Melting point 59°-60° C.
Formula I
r.sub.1 = x = h r.sub.2 = isopropyl
R.sub.3 = C.sub.2 H.sub.5
following the procedure of Example 19 but starting from 13.5 g of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid and 4.9 g of dimethylaminoethanol, 11.2 g of the dimethylaminoethanol salt of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 69°-71° C.
Formula IX
r.sub.1 = r.sub.3 = x = h r.sub.2 = ch.sub.3
a solution of 11 g of [2-methyl-indanyl-(5)]-acetic acid and 7.5 ml of thionyl chloride in 75 ml of benzene is heated at 80° C for 2 hours. The solvent and the excess thionyl chloride are then evaporated in vacuo. The residue obtained is fractionated in vacuo to yield 8.6 g of [2-methyl-indanyl-(5)]-acetic acid chloride in the form of a liquid.
Boiling point 12 mm Hg = 148°-151° C.
Formula I
r.sub.1 = r.sub.3 = x = h
r.sub.2 = ch.sub.3 ##STR32##
a solution of 8.6 g of [2-methyl-indanyl-(5)]-acetic acid chloride in 50 ml of benzene is added dropwise to a solution of 5.4 g of morpholino-ethanol in 150 ml of anhydrous benzene containing 7.7 ml of triethylamine, whilst keeping the reaction mixture at 0° C. After the end of the addition, the reaction mixture is stirred for 2 hours at ambient temperature and is then left to stand overnight. The benzene phase is isolated and the mother liquors are extracted with ether. The combined organic phases are washed carefully with water and dried over sodium sulphate. After concentration in vacuo, the residue is taken up in a mixture of acetone and ether and a solution of hydrogen chloride in ether is added thereto to yield 9.4 g of the hydrochloride of the morpholine-ethyl ester of [2-methyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 107°-110° C.
Formula IX
r.sub.1 = x = h r.sub.2 = r.sub.3 = ch.sub.3
a solution of 11.3 g of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid and 7 ml of thionyl chloride in 100 ml of benzene is heated at 80° C for 2 hours. The solvent and the excess thionyl chloride are then evaporated in vacuo. The oil obtained is used in crude form for the remainder of the operations.
Formula I
r.sub.1 = x = h r.sub.2 = r.sub.3 = ch.sub.3 ##STR33##
following the procedure of Example 21(b) but starting from 7 g of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid chloride, 6.8 g of the morpholino-ethyl ester of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of an oil. On adding 2.7 g of oxalic acid dissolved in ethanol, 7.1 g of the oxalate of the morpholino-ethyl ester of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from isopropanol.
Melting point 140°-145° C.
Formula IX
r.sub.3 = x = h r.sub.1 = r.sub.2 = ch.sub.3
following the procedure of Example 21(a) but starting from 16 g of [2,2-dimethyl-indanyl-(5)]-acetic acid, there are obtained, after distillation of the residue in vacuo, 14.7 g of [2,2-dimethyl-indanyl-(5)]-acetic acid chloride in the form of a liquid.
Boiling point 10 mm Hg = 140°-145° C.
Formula I
r.sub.3 = x = h r.sub.1 = r.sub.2 = ch.sub.3 ##STR34##
following the procedure of Example 21(b) but starting from 14.7 g of [2,2-dimethyl-indanyl-(5)]-acetic acid chloride, a residue is obtained after evaporation of the organic solvents in vacuo; this residue is taken up in a mixture of acetone and ether and a solution of hydrogen chloride in ether is added thereto to yield 16 g of the hydrochloride of the morpholino-ethyl ester of [2,2-dimethyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 145°-150° C.
Formula IX
x = h r.sub.1 = r.sub.2 = r.sub.3 = ch.sub.3
following the procedure of Example 21(a) but starting from 10.2 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid, 10.5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid chloride are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula I
x = h r.sub.1 = r.sub.2 = r.sub.3 = ch.sub.3 ##STR35##
following the procedure of Example 21(b) but starting from 10.5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid chloride, there are obtained, after having taken up the residue obtained in a mixture of acetone and ether and after having added a solution of hydrogen chloride in ether thereto, 12 g of the hydrochloride of the morpholino-ethyl ester of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 140°-142° C.
Formula IX
x = r.sub.2 = h r.sub.1 = cyclohexyl
R.sub.3 = CH.sub.3
following the procedure of Example 21(a) but starting from 10 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid, 10.2 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid chloride are obtained in the form of an oil which is used in crude form for the remainder of the operations.
Formula I
x = r.sub.2 = h r.sub.1 = cyclohexyl
R.sub.3 = CH.sub.3 ##STR36##
following the procedure of Example 21(b) but starting from 10.2 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid chloride, there are obtained, after having diluted the residue obtained with a mixture of acetone and ether and after having added a solution of hydrogen chloride in ether thereto, 8.9 g of the hydrochloride of the morpholino-ethyl ester of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting pont 154°-156° C.
Formula IX
r.sub.2 = x = h r.sub.1 = c.sub.2 h.sub.5
r.sub.3 = ch.sub.3
following the procedure of Example 21(a) but starting from 19.2 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid, 18.5 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid chloride are obtained, after distillation of the residue in vacuo.
Boiling point 10 mm Hg = 170°-175° C.
Formula I
r.sub.2 = x = h r.sub.1 = c.sub.2 h.sub.5
r.sub.3 = ch.sub.3 ##STR37##
following the procedure of Example 21(b) but starting from 16.5 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid chloride, 15 g of the morpholino-ethyl ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of an oil. On adding 5.5 g of oxalic acid dissolved in ethanol, 15.5 g of the oxalate of the morpholino-ethyl ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from ethanol.
Melting point 143°-145° C.
Formula IX
r.sub.2 = x = h r.sub.1 = isopropyl
R.sub.3 = CH.sub.3
following the procedure of Example 21(a) but using 31.7 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, melting point 81°-83° C, described above, there are obtained, after distillation of the residue in vacuo, 30.1 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride.
Boiling point1 mm Hg = 150° C.
Formula I
r.sub.1 = x = h
r.sub.2 = isopropyl
R.sub.3 = CH.sub.3 ##STR38##
following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 3.6 g of dimethylaminoethanol, a residue is obtained after evaporation of the organic solvents in vacuo; this residue is taken up in a mixture of acetone and ether and a solution of hydrogen chloride in ether is added thereto to yield, after recrystallisation of the crystals obtained from acetone, 11.4 g of the hydrochloride of the dimethylaminoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 123°-124° C.
Formula I
r.sub.2 = x = h r.sub.1 = isopropyl
R.sub.3 = CH.sub.3 ##STR39##
following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 4.1 g of diethylaminoethanol, 10 g of the diethylaminoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained, after evaporation of the organic solvents in vacuo; 3.8 g of oxalic acid dissolved in ethanol are added to the above ester to yield, after recrystallisation from isopropanol, 11 g of the oxalate of the diethylaminoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 135°-137° C.
Formula I
r.sub.2 = x = h
r.sub.1 = isopropyl
R3 = ch3 ##STR40##
following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 4.1 g of dimethylamino-α-dimethyl-ethanol, 11 g of the dimethylamino-α-dimethyl-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained; 3.8 g of maleic acid dissolved in acetone are added to the above ester to yield 11.2 g of the maleate of the dimethylamino-α-dimethylethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 92°-95° C.
Formula I
r.sub.2 = x = h
r.sub.1 = isopropyl
R.sub.3 = CH.sub.3 ##STR41##
following the procedure of Example 21(b) but using 14 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and 7.2 g of piperidinoethanol, 15 g of ester are obtained; 5.5 g of oxalic acid dissolved in ethanol are added to the above ester to yield 14 g of the oxalate of the piperidinoethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals, after recrystallisation from ethanol.
Melting point 139°-141° C.
Formula I
r.sub.2 = x = h
r.sub.1 = isopropyl
R.sub.3 = CH.sub.3
r.sub.4 = na
25.5 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are treated with a solution of sodium methylate prepared from 2.5 g of sodium dissolved in 40 ml of methanol. After evaporation of the solvent, the residue is taken up in ether and 23 g of the sodium salt of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of a white powder which is soluble in water.
Formula I
r.sub.2 = x = h
r.sub.1 = isopropyl
R.sub.3 = CH.sub.3 ##STR42##
a solution of 11 g of the sodium salt of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid and 6.9 g of β-chloroethylpyrrolidine in 100 ml of xylene is heated under reflux for 7 hours. After cooling the reaction mixture, the organic phase is washed with water and dried over sodium carbonate. After evaporation of the solvent, a residue weighing 14.3 g is obtained to which a solution of 5 g of maleic acid in acetone is added. 17.4 g of the maleate of the pyrrolidino-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are thus obtained in the form of white crystals.
Melting point 114°-116° C.
Formula I
r.sub.1 = h r.sub.2 = isopropyl
R.sub.3 = CH.sub.3
a solution of 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in 50 ml of anhydrous ether is added dropwise to a suspension of 3.3 g of lithium aluminum hydride in 50 ml of anhydrous ether. After the end of the addition, the reaction mixture is heated under reflux for 3 hours.
After cooling, a saturated aqueous solution of sodium sulphate is added dropwise at 0° C in order to destroy the excess hydride. As soon as the hydride no longer reacts, sodium sulphate is added to the reaction and filtration is effected. The precipitate is washed carefully with ether the filtrates are combined and the ether is evaporated. 9.5 g of 2-methyl-β-[2-isopropyl-indanyl-(5)]-ethanol are thus obtained in the form of white crystals.
Melting point 45° C.
Formula I
r.sub.1 = h r.sub.2 = c.sub.2 h.sub.5
r.sub.3 = ch.sub.3
following the procedure of Example 33 but using 12.8 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid, there are recovered, after vacuum distillation of the residue obtained, 10 g of 2-methyl-β-[2-ethyl-indanyl-(5)]-ethanol in the form of a colourless oil.
Boiling point1 mm Hg = 130°-132° C.
Formula I
r.sub.1 = h r.sub.2 = ch.sub.3
r.sub.3 = h
following the procedure of Example 33 but using 3.5 g of [2-methyl-indanyl-(5)]-acetic acid, there are recovered, after vacuum distillation of the residue obtained, 2.6 g of β-[2-methyl-indanyl-(5)]-ethanol in the form of a colourless oil.
Boiling point0.5 mm Hg = 115° C.
R.sub.1 = H R.sub.2 = isopropyl
A mixture of 100 g of [2-isopropyl-indanyl-(5)]-methyl ketone, 22.2 g of sulphur and 75 g of morpholine is heated at 140° C for 12 hours. Thereafter, the reaction mixture is concentrated in vacuo and is then taken up in 200 ml of 95° strength ethanol. The crystals formed are filtered off and washed with a small amount of cold 95° strength ethanol. 95 g of [2-isopropyl-indanyl-(5)]-acetic acid morpholinethioamide are thus obtained in the form of light yellow crystals.
Melting point 120° C.
Formula I
r.sub.1 = r.sub.3 = r.sub.4 = h r.sub.2 = isopropyl
A solution of 95 g of [2-isopropyl-indanyl-(5)]-acetic acid morpholinethioamide in 125 ml of acetic acid and 175 ml of hydrochloric acid (d = 1.18) is heated under reflux for 18 hours.
The reaction mixture is then poured onto ice and the organic products are extracted with ether. After the ether has been washed carefully with water and dried over sodium sulphate, it is evaporated in vacuo. After recrystallisation of the residue obtained from petroleum ether, 63 g of [2-isopropyl-indanyl-(5)]-acetic acid are isolated in the form of white crystals.
Melting point 80°-81° C.
Formula I
r.sub.1 = h r.sub.2 = isopropyl
R.sub.3 = H
following the procedure of Example 33 but using 25 g of [2-isopropyl-indanyl-(5)]-acetic acid, 20.5 g of β-[2-isopropyl-indanyl-(5)]-ethanol are obtained in the form of white crystals, after recrystallisation from pentane.
Melting point 41°-42° C.
The pharmacological properties of the products of the invention are illustrated by the following experimental results.
The products to be tested are administered orally to batches of 12 SPF male rats, OFA strain, weighing 120-130 g, 2 hours and 30 minutes (1/2 dose each time) before the subcutaneous plantar injection of 0.05 ml of a 1% strength solution of carraghenine. The volume of the back paw which received the phlogogenic agent is measured at regular intervals. The 50% effective dose is calculated at the moment of greatest swelling of the controls.
The results are given in Tables I to IV below, in which the percentage reduction in the inflammation is noted.
TABLE I
______________________________________
mg/kg
oral admini-
Ex.
stration 1 and 2 Ex. 3 Ex. 4
Ex. 6 Ex. 7
Ex. 8
Ex. 9
______________________________________
8 -- -- -- -- 29 -- --
16 -- -- -- -- 43 -- 47
32 -- -- 10 -- 61 17 68
64 15 24 19 16 73 23 80
128 42 36 47 39 75 52 --
256 88 56 80 44 -- 62 --
______________________________________
ED.sub.50 mg/kg
130 200 120 >256 22 150 17
______________________________________
ED.sub.50 = 50% effective dose?
OA (sic) = oral adiminstration
TABLE II
__________________________________________________________________________
Ex. Ex.
Ex.
Ex. Ex.
Ex.
Ex. Ex.
Ex.
Ex.
mg/kg
11 12 13 14 15 16 17 18 19 20
__________________________________________________________________________
4 -- -- -- -- -- -- -- -- 25 --
8 -- -- -- -- -- -- -- -- 20 --
16 -- 15 23 11 11 4 13 31 44 16
32 4 23 29 5 20 20 24 54 48 24
64 8 49 37 16 27 37 30 61 63 25
128 13 71 47 17 41 61 38 66 67 38
256 13 80 51 31 68 94 43 77 82 37
512 32 -- -- 34 72 -- -- -- -- --
__________________________________________________________________________
ED.sub.50
mg/kg
>512
70 200
>512
160
73 >256
36 30 >256
OA
__________________________________________________________________________
ED.sub.40 = 50% effective dose
OA = oral administration
TABLE III
__________________________________________________________________________
Ex.
Ex.
Ex.
Ex.
Ex. Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
mg/kg
21 22 23 24 25 26 27 28 29 30 32
__________________________________________________________________________
4 -- -- -- -- -- -- 29 37 12 10 19
8 -- -- -- -- -- -- -- -- -- -- --
16 -- 17 13 7 26 38 54 31 35 32 21
32 17 7 9 21 28 47 -- -- -- -- --
64 25 12 30 36 7 54 61 66 45 55 59
128 52 11 50 50 12 68 64 72 72 47 55
256 68 34 55 57 10 70 76 79 65 52
512 -- 52 90 73 -- -- -- -- -- -- --
__________________________________________________________________________
ED.sub.50
130
480
140
142
>256
40 22 24 55 -- 65
mg/kg
OA
__________________________________________________________________________
ED.sub.50 = 50% effective dose
OA = oral administration
TABLE IV
______________________________________
mg/kg
oral administration
Ex. 33 Ex. 34 Ex. 35 Ex. 37
______________________________________
8 0 -- -- --
16 13 46 43 0
32 34 42 42 1
64 52 51 56 21
128 58 60 76 41
256 63 61 89 30
______________________________________
ED.sub.50 85 50 35 >256
mg/kg
oral administration
______________________________________
OA = oral administration
ED.sub.50 = 50% effective dose
The products tested are administered orally to batches of 6 male mice (SPF1, OF1 strain) weighing 19-20 g.
1 hour later, 0.3 ml of a 0.02% strength solution of phenylbenzoquinone is injected intraperitoneally into each mouse and, from the 5th to the 10th minute after the latter treatment, the number of pain reactions (abdominal twistings) is counted.
Table V to VIII below give the percentage inhibition of these reactions.
TABLE V
______________________________________
mg/kg
oral
admini-
Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.
stration
1 and 2 3 4 5 6 7 8 9
______________________________________
8 -- -- -- -- -- 17 -- --
16 25 33 6 -- 28 61 -- --
32 28 51 33 -- 41 96 10 28
64 67 66 70 32 59 -- 67 26
128 89 66 99 -- 78 -- 73 79
256 94 94 -- 58 72 -- 90 97
______________________________________
ED.sub.50
mg/kg 43 33 40 ≈150
40 14 70 78
OA
______________________________________
ED.sub.50 = 50% effective dose
OA = oral administration
TABLE VI
__________________________________________________________________________
mg/kg
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
OA 11 12 13 14 15 16 17 18 19 20
__________________________________________________________________________
2 -- -- -- -- -- -- -- 18 -- --
4 -- -- -- -- -- -- -- 27 5 --
8 -- -- -- -- 14 13 -- 58 31 --
16 -- -- 15 -- 18 30 -- 75 54 --
32 15 9 30 20 68 77 -- 95 82 26
64 29 20 71 35 91 96 28 -- 96 --
128 58 46 83 52 -- -- 70 -- -- 27
256 59 67 -- 62 -- -- 83 -- -- 74
512 83 75 -- 93 -- -- 100
-- -- 100
__________________________________________________________________________
ED.sub.50
140
175
46 110
23 19 100
6.5
14 175
mg/kg
__________________________________________________________________________
ED.sub.50 = 50% effective dose
OA = oral administration
TABLE VII
__________________________________________________________________________
mg/kg
Ex.
Ex.
Ex. Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
OA 21 22 23 24 25 26 27 28 29 30 32
__________________________________________________________________________
4 -- -- -- -- -- -- -- 21 -- -- --
8 -- -- 1 0 -- 17 7 20 -- -- 6
16 -- -- 20 24 13 52 42 40 8 11 47
32 -- 19 36 32 19 69 69 66 43 32 79
64 2 73 82 53 50 94 94 86 57 73 99
128 51 86 45 97 64 -- 99 -- 86 99 --
256 71 98 45 -- -- -- -- -- 96 -- --
512 81 -- -- -- -- -- -- -- -- -- --
__________________________________________________________________________
ED.sub.50
200
45 >256
35 80 18 23 20 50 37 18
mg/kg
__________________________________________________________________________
ED.sub.50 = 50% effective dose
OA = oral administration
TABLE VIII
______________________________________
mg/kg
OA Ex. 33 Ex. 34 Ex. 35 Ex. 37
______________________________________
2 6 -- -- --
4 25 -- -- --
8 42 -- -- --
16 68 -- -- 0
32 90 12 10 40
64 -- 22 27 55
128 -- 60 69 62
256 -- 94 95 81
______________________________________
ED.sub.50 mg/kg
9 95 87 60
OA
______________________________________
ED.sub.50 : 50% effective dose
OA : oral administration
Claims (8)
1. A compound of the general formula ##STR44## in which: X represents a hydrogen or halogen atom; R1 and R2, which may be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms; R3 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; and n is an integer of 1 to 5; or a pharmaceutically acceptable addition salt of said compound.
2. A compound according to claim 1 in which R1 and R2, which may be identical or different, each represents a hydrogen atom or a methyl, ethyl, isopropyl or cyclohexyl group.
3. A compound according to claim 1 in which R3 represents a hydrogen atom or a methyl or ethyl group.
4. A compound according to claim 1 in which X represents a hydrogen atom.
5. A compound according to claim 1 in which n is 2.
6. The compound of claim 1 which is the oxalate of the morpholino-ethyl ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid.
7. A composition for treating inflammations, algias, rheumatisms or pain syndromes comprising a therapeutically effective amount of at least one compound as defined in claim 1 or a pharmaceutically acceptable addition salt thereof and a pharmaceutically acceptable carrier or diluent.
8. A method of treating inflammations, algias, rheumatisms or pain syndromes in animals which method comprises administering to the animal a therapeutically effective amount of at least one compound as defined in claim 1.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| UK5726/74 | 1974-02-07 | ||
| GB5726/74A GB1492175A (en) | 1974-02-07 | 1974-02-07 | Indane derivatives |
| UK37220/74 | 1974-08-23 | ||
| GB3722074 | 1974-08-23 | ||
| GB5429274 | 1974-12-16 | ||
| UK54292/74 | 1974-12-16 | ||
| US54609575A | 1975-01-31 | 1975-01-31 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US54609575A Division | 1974-02-07 | 1975-01-31 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/788,033 Division US4182896A (en) | 1974-02-07 | 1977-04-15 | Indane derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4069326A true US4069326A (en) | 1978-01-17 |
Family
ID=27447465
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/690,390 Expired - Lifetime US4088787A (en) | 1974-02-07 | 1976-05-27 | Indane ethanols |
| US05/690,391 Expired - Lifetime US4069326A (en) | 1974-02-07 | 1976-05-27 | Morpholino containing indane acetic acid esters |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/690,390 Expired - Lifetime US4088787A (en) | 1974-02-07 | 1976-05-27 | Indane ethanols |
Country Status (1)
| Country | Link |
|---|---|
| US (2) | US4088787A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5525617A (en) * | 1994-08-24 | 1996-06-11 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| US5534546A (en) * | 1993-03-31 | 1996-07-09 | Kagome Kabushiki Kaisha | Indene derivatives and antimicrobial agents containing same |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4281017A (en) * | 1978-09-16 | 1981-07-28 | Lilly Industries Limited | Pharmaceutically active indane derivatives |
| US5442124A (en) * | 1989-06-30 | 1995-08-15 | Firmenich Sa | Process for the preparation of novel aromatic compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3018222A (en) * | 1956-08-28 | 1962-01-23 | Ravensberg G M B H | Central stimulant and appetite depressant composition |
| US3452085A (en) * | 1966-02-11 | 1969-06-24 | Carbo Erba Spa | Alpha-(5-indanyl)-butyric acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3660311A (en) * | 1970-01-09 | 1972-05-02 | Int Flavors & Fragrances Inc | Novel fragrance methods and compositions |
| FR2139628A1 (en) * | 1971-05-28 | 1973-01-12 | Lipha | 5-(4-aryl piperazino-alkyl and alkylene) indans - with tranquillizing activity |
-
1976
- 1976-05-27 US US05/690,390 patent/US4088787A/en not_active Expired - Lifetime
- 1976-05-27 US US05/690,391 patent/US4069326A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3018222A (en) * | 1956-08-28 | 1962-01-23 | Ravensberg G M B H | Central stimulant and appetite depressant composition |
| US3452085A (en) * | 1966-02-11 | 1969-06-24 | Carbo Erba Spa | Alpha-(5-indanyl)-butyric acid |
Non-Patent Citations (1)
| Title |
|---|
| Erba, "Chem Abstracts", vol. 69, (1968), No. 35925g. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5534546A (en) * | 1993-03-31 | 1996-07-09 | Kagome Kabushiki Kaisha | Indene derivatives and antimicrobial agents containing same |
| US5525617A (en) * | 1994-08-24 | 1996-06-11 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| US4088787A (en) | 1978-05-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3176019A (en) | Substituted aminobutynyl acetates | |
| US3293263A (en) | Diphenylbenzocycloalkenes | |
| CA1153384A (en) | 6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives | |
| US4012524A (en) | [1-Hydroxy-5-indanyloxy (or thio)]-alkanoic acids | |
| US4478750A (en) | 1-Phenyl-azepinoindoles | |
| US4069326A (en) | Morpholino containing indane acetic acid esters | |
| US4182896A (en) | Indane derivatives | |
| US4017517A (en) | 2-(Trisubstituted benzoyl)-propionic acid and a method for the production thereof | |
| US4254056A (en) | 2-Aminomethyl phenol derivative and process for preparing thereof | |
| US3625970A (en) | 1-(disubstituted phenyl or benzyl)-1h-indazol-3-yloxyacetic acid | |
| US3414582A (en) | 4-(dialkylaminoethoxyphenyl) pyrazoles | |
| US4245099A (en) | 2-Acyl-6-aminomethylphenol derivatives | |
| US3073826A (en) | 3-pyrrolidylmethyl-4-quinazolones | |
| US3882174A (en) | Amides of 4-(4{40 -biphenylyl)-butyric acid and its 4-hydroxy and 4-oxo derivatives | |
| US2538793A (en) | Alkamine esters of cyclopentylalkylacetic acids | |
| US4029787A (en) | Basically substituted 3-sulfamoylbenzoic acid derivatives and process for their preparation | |
| CA1063618A (en) | Indane derivatives | |
| US4420482A (en) | 1,4-Bis(acetylsalicyloyloxy)piperizine derivatives | |
| US3651084A (en) | Substituted phenylalkanoic acids | |
| US4243665A (en) | 2-Heterocyclylalkyl-6-methoxy-naphthalenes | |
| US3965106A (en) | 3-Phenoxypropylamine derivatives | |
| US4851425A (en) | Cyclopentapyrazole and tetrahydroindazole compounds and their use as anti-inflammatory and anti-allergic agents | |
| Clark et al. | The preparation of some thiochroman-3-ones and derivatives | |
| US4232039A (en) | Phenyl- or cycloalkyl-benzo-oxacyclic compounds | |
| US4029699A (en) | 3,(2,4,5-Trisubstituted benzoyl)-propionic acid and the salts thereof |